A brief introduction of main mechanosensitive ion channels in mammalian

Cells convert mechanical stimuli into electronic and chemical signals through mechanically activated ion channels [1]. Detailed studies of various known mechanosensitive ion channels and active discovery of unknown mechanosensitive ion channels are important for discussing mechanical-signaling mechanisms. Mechanically sensitive ion channels in mammals are mainly tandem-pore-domain potassium channels (K2P), the Piezo family, the transient receptor potential (TRP) channel family, the epithelial Na+ channel/degenerin (ENaC/DEG) superfamily and the acid-sensing ion channels (ASIC) [1]. The K2P family consists of three mechanosensitive ion channels: TREK-1, TREK-2, and TRAAK. Mechanical forces can activate trough currents and stretch currents [2]. K2P is expressed in sensory neurons, promotes cell hyperpolarization and reduces the conductance of non-selective cationic mechanical sensors [3]. Piezo family are very conservative compared to other known channels, Piezo are widely involved in various mechanical conduction processes and in regulating blood pressure and disease. Chemicals, lipid signaling molecules, and physical stimuli can activate TRP channels, causing them to involved in thermal, chemical, mechanical, and permeative processes [4]. TRPV4 is involved in mechanical transduction processes and in the regulation of osmolality, vascular tone, and pain perception [5]. The DEG family was first identified in the mutants MEC-4 and MEC-10 of the Caenorhabditis elegans. In mammals, ENaC and the ASIC channel family share homology with MEC-4 and MEC-10 channels in Caenorhabditis elegans, sensing pain and blood pressure changes [6, 7]. ENaC channels formed by α-, β-, and γ-subunits are typical mechanical sensors in vertebrates with roles in regulating blood pressure and electrolyte/fluid homeostasis [8]. There may be mechanosensitive ion channels that have not yet been identified, and the molecular mechanisms of the mechanical-sensing process need to be further investigated.

The regulation of Piezo1 in cardiovascular function and pathological responses

The role of Piezo1 in regulating the blood pressure

Endothelial cells are continuously undergoing various forms of mechanical stimuli, such as changes in the flow of blood vessels due to changes in blood pressure, causing endothelial cells to sense mechanical forces. Piezo1 is an important mechanosensitive cation channel that occurs in large numbers in vascular endothelial cells and lymphatic vessels. Piezo1 in mice senses mechanical stimuli and generates mechanically activated cationic currents [9, 10]. Endothelial production of nitric oxide (NO) regulates vasoconstriction and maintains blood pressure homeostasis. Mechanical stimuli generated by blood flow activate Piezo1 to induce endothelial NO formation and increase Ca2+ concentration. Piezo1 activates the endothelial nitric oxide synthase (eNOS)/AKT signaling pathway with the assistance of calmodulin, which induces the production of NO and release of ATP, resulting in vasodilation and a reduction in systolic blood pressure [11]. If Piezo1 is absent from endothelial cells, endothelium-dependent responses induced by blood flow shear forces are impaired, eNOS activity is reduced, and vasodilation is impaired, ultimately leading to arterial hypertension. Piezo2 and Piezo1 coactivate pressure receptors in the carotid arteries and aorta to regulate acute blood pressure changes [12]. Double deletion of the Piezo 1/2 gene inhibits pressure receptor reflexes. This leads to a nonbenign increase in blood pressure [13].

Piezo1 is involved in the remodeling of blood vessels in atherosclerosis

Regular beating of the heart results in increased blood flow and mechanical pressure stimulation of vascular endothelial cells and vascular smooth muscle cells. Mechanical stress is determined by vascular pressure. Circulation is the main source of blood flow shear. Shear affects the structure and function of the vascular intima and is involved in the development of atherosclerosis [14]. Piezo1 is an important mechanosensitive cation channel that regulates angiogenesis, development, and regeneration [15,16,17]. The activation of Piezo1 by mechanical stimulation increases Ca2+ inflow, which activates calpsin-2 (CAPN2), matrix metalloproteinase-2 (MMP2) and membrane type 1 matrix metalloproteinase (MT1-MMP), resulting in corresponding biological functions, including endothelial cell alignment and migration, vascular development, maturation, regeneration and remodeling18. Piezo1 contributes to early vascular development [18]. Endothelium-specific knockout of Piezo1 impairs vascular maturation and leads to embryonic death [19], suggesting that Piezo1 is essential for early vascular development. In endothelial cells, blood flow activates Piezo1. This leads to the phosphorylation of AKT and eNOS through P2Y2/Gq/G11 signaling, accompanied by the release of ATP [11]. Both laminar and turbulent flow can generate mechanical stress and activate Piezo1 [20]. Piezo1 activation by laminar flow mediates eNOS activation and NO release, which can ameliorate atherosclerosis. Conversely, Piezo1 activation by turbulence increases endothelial inflammatory responses and promotes atherosclerosis [21] (Fig. 1).

Fig. 1
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Different blood flow characteristics affect Piezo1 regulation of cardiovascular function and pathological changes

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Electrophysiologic and ionic changes during ischemia

Ischemia causes cellular depolarization, resulting in an increase in extracellular potassium concentration [K+]o, ATP-sensitive inward-rectifying potassium current (IKATP) peak and acetylcholine-activated potassium current (IKACh), as well as a decrease in action potential duration, thereby accelerating the repolarization process. After ischemia, there was a slight increase in cellular excitability. Within 2–3 min, the negative cellular resting voltage decreased from approximately − 85 to − 60 mV, resulting in the inhibition of Na+ channel activity and the action potential (AP) conduction, which decreased the conduction velocity to approximately 0.03 cm/ms and emergence of slower inactivating sodium current, leading to a decreased cellular excitability and prolonged effective refractory period [22]. Elevated [K+]o leads to a lengthening of the post-repolarization refractoriness. This effect is most pronounced when the IKATP reaches its peak. Additionally, both the maximum rate of rise of the AP and the maximum transmembrane voltage are reduced [23]. The ventricular activation time is prolonged from 80–100 to 200–300 ms [22].

Ischemia shifts cellular metabolism towards anaerobic conditions, increases NADH, promotes Na+/Ca2+ Exchangers (NCX) activities, inhibits sarcoplasmic reticulum Ca-ATPase (SERCA) activities, decreases calcium transient (CaT), increases diastolic intracellular calcium concentration [Ca2+]i and disrupts [Ca2+]i homeostasis [24, 25]. The use of ORM-10103, a specific inhibitor of NCX, was found to reduce [Ca2+]i, alleviate the negative effects of ischemia/reperfusion on cells, and ameliorate the reduction in AP and CaT after reperfusion, but still caused arrhythmias [25].

The electrocardiogram pattern of ischemia is characterized by reduced R-wave amplitude, ST-segment elevation, T-wave inversion, prominent Q-wave, shortened RR interval, prolonged QT interval, etc. [26]. Additionally, cardiac output, stroke volume, fractional shortening, and ejection fraction are all impaired, and there is a delay in ventricular depolarization and repolarization, which disturbs the activity of the autonomic nervous system and leads to arrhythmia [26].

Arrhythmias are primarily caused by two types of activity: early after depolarizations (EAD) and delayed after depolarizations (DAD), which are related to calcium overload and catecholamine secretion. EAD occur in and out of the sinoatrial node through activation of ion channels such as transient outward potassium current. Ventricular tachycardia typically occurs within 2–10 min after ischemia, while ventricular fibrillation usually occurs within 20–30 min [22]. Studies of electrophysiological and ionic changes during cardiac ischemia have contributed to the important role of mechanosensitive ion channels in the cardiovascular system.

The role of Piezo1 in ischemic heart injury

Ischemic heart injury initiates with changes in the mechanical environment of the heart. Piezo1 is expressed in the heart and is involved in mechanical transduction processes [27, 28]. Piezo1 mediates pathological cardiac hypertrophy by regulating the expression levels of calmodulin and calpain through a positive feedback mechanism [27]. Piezo1 is upregulated in the ischemic heart and regulates Ca2+ production and reactive oxygen species (ROS) signaling in the cardiomyocyte through a positive feedback mechanism. This allows the heart to adapt to pathological mechanical load [29]. Piezo1 mediates pathological cardiac hypertrophy by regulating the expression levels of calmodulin and calpain through a positive feedback mechanism. Cardiac Piezo1 expression increases after myocardial infarction, associated with ventricular remodeling and the development of myocardial hypertrophy. Inhibition of Piezo1 expression improves cardiac function and alleviates myocardial hypertrophy. Ischemic injury-induced myocardial fibrosis is triggered by an increase in extracellular matrix (ECM) stiffness [30]. Piezo1, in conjunction with integrin β1, acts as an initial signaling molecule in the activation of cardiac fibroblasts. Piezo1 and integrin β1 form a mutually reinforcing positive feedback loop in which increased ECM hardness promotes expression of both. As the expression levels of Piezo1 and integrin β1 increased, the stiffness of the ECM and the feedback strength of the loops increased, further accelerating the process of cardiac fibrosis [30]. Piezo1 in cardiac fibroblasts activates the p38MAPK signaling pathway, linking Ca2+ entry to interleukin-6 (IL-6) secretion, promoting cardiac hypertrophy and remodeling [31] (Table 1).

Table 1 Piezo1 regulates cardiovascular disease
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The role of TRP channels in regulating the cardiovascular function and pathological processes

TRP channels play a role in the development of cardiovascular disease and regulate cardiovascular function.

TRPP1 channels sense blood flow in the vasculature, and blood flow stimulates TRPP1 in endothelial cells, activating small conductance and intermediate Ca2+-activated potassium channels (SK/IK), as well as activating eNOS, resulting in vasodilation and reduced blood pressure [39]. TRPP1/2 is expressed on the endothelial membrane of cardiomyocytes, and cardiac-specific knockout of TRPP1 resulted in abnormally increased blood pressure in mice [40]. In the heart, simultaneous expression of both forms large conductance non-selective cation channels. TRPP2-deficient mice are embryonic lethal and exhibit cardiac septal defects [41]. Mutations in TRPP2 lead to autosomal dominant polycystic kidney disease (ADPKD), and patients with ADPKD suffer from cardiac dysplasia manifested by septal morphology or mitral valve prolapse, suggesting a certain role for TRPP1/2 in cardiac development [42].

During cardiac remodeling in ischemic cardiomyopathy, the Ca2+ response is dramatically altered, and some mechanosensitive cation channels are acting to mediate the response. TRPC3 channels are overexpressed and mediate Ca2+ influx into cardiomyocytes in hypertrophied hearts [43]. Angiotensin II (Ang II) induces cardiac hypertrophy and activates TRPC1/3/4/6 [44]. Dual inhibition of TRPC1 and TRPC4 expression ameliorates cardiac hypertrophy [45]. Inhibition of TRPC3/6 expression in myocardial infarction or transverse aortic constriction (TAC)-induced cardiac hypertrophy results in reduced myocardial infarction, decreased levels of cardiac fibrosis, and improved cardiac function [46]. TRPC3 interacts with nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (Nox2) to promote ROS generation and increase levels of oxidative stress in the heart. Inhibition of TRPC3 reduces Nox2 expression and ROS production, thereby improving cardiac function [47]. Studies have shown that cardiac TRPC6 is activated by stretch, which increases myocardial Ca2+ concentration and endothelin-1 expression, leading to the onset and development of arrhythmias [48]. In mice with MLP (-/-)-induced dilated cardiomyopathy, TRPC3 activates Ca2+/calmodulin-dependent kinase II (CaMKII). Inhibition of TRPC3 attenuates this process and reduces Rac1-mediated increase in ROS production, ameliorating cardiomyopathy [49]. Inhibition of TRPC3 can also reduce apoptosis in endothelial cells and has atherosclerosis-protective effects. TRPC channels are involved in regulating pathological processes such as angiogenesis, arterial atherosclerosis, inflammatory responses, and hypertension [50]. TRPC1 is overexpressed in patients who have undergone coronary artery bypass graft surgery and in pigs with coronary artery injury, and the over-proliferation of smooth muscle cells promotes Angiogenesis [51]. Hypertension is associated with changes in TRPC channel activity. In hypertensive patients, there is an increase in vascular expression of TRPC1/3/5, which disrupts Ca2+ homeostasis [52,53,54]. Additionally, TRPC6 knockout mice exhibit a hypertensive phenotype, and it is hypothesized that TRPC3 negatively regulates TRPC6 expression through a feedback mechanism [50]. In myocardial hypertrophic and spontaneously hypertensive rats, the expression of TRPM4 is increased, causing a dramatic increase in Ca2+ release from atrial cardiomyocytes and an imbalance in Ca2+ homeostasis, followed by delayed depolarization and changes in ECG signals, leading to myocardial hypertrophy-associated arrhythmias [55].

TRPV channels are critical in the regulation of cardiac structure and function.TRPV1 is expressed in cardiomyocytes, vascular endothelial cells, and smooth muscle cells and is involved in the regulation of calcium in cardiomyocyte differentiation during early heart development [56]. The expression of TRPV1 is increased in TAC-induced myocardial hypertrophy, leading to elevated levels of cardiac inflammatory markers TNFα and IL-6, and activation of the NF-κB signaling pathway, which promotes cardiac hypertrophy [57]. Cardiac fibrosis is related to TRPV1/2/3, and TRPV1 deletion leads to an increase in cardiac collagen fibers and increased expression levels of the fibrosis-related genes TGFβ1, Col1a1, and Col3a1 [58]. TRPV2 and TRPV3 are ion channels that play important roles in the heart. TRPV2 converts mechanical signals into electrochemical signals that perform biological functions in response to mechanical stimuli [59]. Knockout of TRPV2 in cardiomyocytes results in embryonic death. TRPV3 increases intracellular Ca2+ concentration, activates CaMKII, Calcineurin (CaN), and NFATc3, and is involved in the development of pathological cardiac hypertrophy [60]. In cardiac hypertrophy induced by abdominal aorta coarctation (AAC), rather than physiological cardiac hypertrophy induced by regular exercise, the expression of TRPV3 and hypertrophic markers brain natriuretic peptide (BNP) and β-myosin heavy chain (β-MHC) has increased [61]. In an in vitro model of fibrosis induced by Ang II, inhibition of TRPV3 resulted in a downregulation of Collagen I and Collagen III, as well as the expression of cell cycle protein E and cell cycle protein-dependent kinase 2 (CDK2) [62]. Similarly, TRPV4 activates eNOS in the same way as TRPP1 to regulate vascular tone [63]. Knockout of TRPV4 results in loss of vasodilator capacity by impairing the endothelium-dependent hyperpolarization (EDH) process [64] (Fig. 2).

Fig. 2
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TRP channel regulate cardiovascular function and pathological processes

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Exercise plays an important physiological function in cardiovascular by regulating Piezo1 and TRP channels

The cardiovascular benefits of regular moderate exercise are well-documented, regardless of the type of exercise [65]. However, overtraining can lead to a decrease in cardiovascular function. The exercise done by competitive athletes causes serious cardiac remodeling leading to increase arrhythmia development. Dogs trained to exercise at a high level for extended periods of time are at a greater risk of developing arrhythmias compared to dogs that are sedentary [66]. They had prolonged cardiac repolarization times, increased repolarization instability, and slight ventricular fibrosis compared to sedentary dogs [66]. Competitive athletes commonly develop various heart rate arrhythmias such as sinus bradycardia, premature beats, and ventricular tachycardia, called “athlete’s heart” [67]. A study found that after inducing physiologic cardiac hypertrophy through 12 weeks of swimming training, rats showed increased cardiac output, decreased long-term QT variability, and increased abnormal ventricular beats, suggesting arrhythmic events. This may be due to increased sarcoplasmic reticulum Ca2+ content disrupting cardiac calcium homeostasis [68]. Therefore, excessive exercise may be detrimental to the improvement of cardiovascular function and the rehabilitation of clinical patients. The amount, duration, and mode of exercise should be properly adjusted accordingly for different cardiovascular risk factors. However, there is currently no personalized exercise prescription available and there is an urgent need for an in-depth study of the relevant molecular mechanisms. We have summarized the role of different exercise modes in regulating the physiological functions of Piezo1 and TRP in Table 2. Hypertrophic cardiomyopathy is a significant factor affecting the careers of athletes, and further research is needed to develop exercise training programs for competitive athletes and to consider how to train for positive cardiac remodeling. Additionally, accurate risk assessment and the development of individualized exercise plans for sedentary individuals with hypertrophic cardiomyopathy is an issue that needs to be further examined [69]. Research into the mechanisms of exercise cardio-protection provides a molecular basis for the selection of appropriate exercise programs for different groups.

Table 2 Exercise regulates the physiological functions of Piezo1 and TRP in different tissues
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Exercise activates vascular endothelial cell Piezo1 to exert its physiological function

Exercise has been shown to be beneficial for cardiovascular disease. Piezo1 acts as an “exercise sensor” that regulates cardiovascular homeostasis by improving vasoconstriction and diastolic function, improving blood redistribution in the body during exercise, and increasing physical fitness in adults [70]. During whole body physical activity, Piezo1 links communication between endothelial cells and mesenteric vascular smooth muscle cells, inducing vasoconstriction, inhibiting EDH, and increasing blood pressure. Endothelium-specific depletion of Piezo1 inhibits the increase in blood pressure during physical activity and reduces exercise capacity [19, 70]. Exercise increases blood flow, thereby increasing blood flow shear, activating Piezo1 and paracrine signaling of eNOS/platelet reactive protein-2 (TSP2), and maintaining capillary density and endothelial microcirculatory stability. These findings suggest a link between Piezo1 and muscle work capacity and physical performance. The study found that endothelial-specific knockdown of Piezo1 inhibits the eNOS/TSP2 signaling pathway, leading to increased endothelial cell apoptosis in muscle micro vessels, reduced capillaries, and decreased physical capacity [71].

Exercise modulates cardiac Piezo1 activity and its physiological function

Exercise can increase the rate of myocardial contraction and stroke volume, and stretch and shear stress can strongly stimulate myocardial and endothelial tissue. At the molecular level of the cardiac system, Piezo1 senses pressure and stretch stimuli, generating appropriate mechanical signals that regulate cell contractility and other physiological properties [72]. Piezo1 responds differentially to varying degrees of mechanical stimulation, and appropriate mechanical forces activate Piezo1 to upregulate the expression of SERCA2 and eNOS, thereby increasing cardiac contractility [72, 73]. Exercise leads to increased cardiac activity, and the mechanosensory system senses cardiac activity and participates in cardiac mechanical transduction activities that regulate changes in cellular function. At the molecular level of the cardiac system, Piezo1 senses pressure and stretch stimuli, generating appropriate mechanical signals that regulate cell contractility and other physiological properties [74]. A study demonstrated that Piezo1 is expressed in myotubes. In cultured mouse myotubes, Yoda1 chemically activates Piezo1 channels to stimulate IL-6 expression. Inhibition of Piezo1 reduced IL-6 secretion. It is believed that Piezo1 activation is responsible for the increased secretion of muscle factors during myocardial diastole during exercise [75].

Exercise regulates TRP channels expression and its physiological function

Cardiorespiratory responses are regulated by exercise muscle afferent feedback during exercise. Studies have shown that TRPV1 and COX-2 expression is upregulated and exercise muscle afferent feedback is enhanced during 5 min of cycling exercise at 65% peak workload in heart failure patients with reduced ejection fraction (HFrEF) [76]. Additionally, TRPV2 plays a role in regulating the cardiac stress response, maintaining cardiac structural integrity, and regulating cardiac Ca2+ flow in both healthy and pathological conditions. TRPV2-deficient mice lose the ability to perform aerobic exercise, and voluntary wheel running activities impairs cardiac function by reducing cardiomyocyte volume, stroke volume and ejection fraction compared to wild mice [77]. Furthermore, the cardioprotective effects of exercise were nullified in knockout mice, and the heart’s adaptive response to exercise stimuli was diminished [78]. TRPC3 activates downstream signaling molecules such as Ca2+-activated protein kinase C (PKC) and regulates Nox2 activity in the heart in response to mechanical stimuli. Knockdown of TRPC3 inhibits Adriamycin-induced increase in Nox2, reduces ROS production, and protects cardiac function. Physical exercise reduced TRPC3 and Nox2 in mouse hearts and similarly improved cardiac function [47]. Exercise is widely recognized as a preventative measure and treatment for diet-related diseases, reducing the risk of illness. In mice fed a high-fat diet, Voluntary wheel running exercise was found to reduce levels of TRPA1 and AKAP150. AKAP150 was found to regulate the membrane movement of TRPV1, and TRPA1 was found to co-localize with and act through TRPV1. These findings suggest that membrane movement of TRP channels may be involved in the mechanism by which exercise benefits high-fat-fed mice [79]. A link between exercise-stimulated mechanosensitive ion channels and motility factors has been found. In endothelial cells, activation of TRPV4 increases intracellular calcium concentration, resulting in vasodilation. TRPV4 mediates Irisin-induced Ca2+ influx and endothelium-dependent vasodilation, which protects vascular function [80] (Table 2, Fig. 3).

Fig. 3
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Exercise modulates Piezo1 and TRP channels to exert cardioprotective effects in normal and pathological hearts

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Advances in mechanism research of exercise modulation of Piezo1 and TRP channels to improve cardiovascular function

Exercise and Piezo1 downstream signaling pathway mechanisms

Piezo1 plays a wide range of roles in cardiovascular biology, where it generates clear connections with multiple signaling pathways involved in the regulation of cardiovascular activity.

AKT/eNOS signaling pathway

Piezo1 activates eNOS at Ser1177 and Ser635, resulting in increased NO production and leading to vasodilation. At Ser635, shear-activated Piezo1 stimulates adrenomedullin to bind to Gαs-coupled receptors, which activates protein kinase A (PKA) and subsequently eNOS via the second messenger cAMP [87]; At Ser1177, mechanical stimulation activates Piezo1 to couple with P2Y2 receptors via Gq/G11 on the cell membrane. This increases levels of the endothelial cell adhesion proteins PECAM-1 and VE-cadherin, activates the AKT signaling pathway, and leads to NO production through eNOS phosphorylation. Piezo1 is activated by shear in blood flow, leading to an increase in Ca2+ influx and ATP release via pannexin [11]. This process has been confirmed by studies conducted by Cinar [88]. The sudden increase in blood flow causes an increase in cellular Ca2+ concentration, which activates calmodulin and eNOS, resulting in vasodilation and constriction [89].

NF-κB signaling pathway

Activation of Piezo1 by flow shear in laminar and turbulent flow has different effects on vascular physiology. Laminar flow stimulates endothelial cells to align and grow in the direction of blood flow and exert biological functions through the eNOS signaling pathway [90]. In contrast, turbulent flow generates oscillatory shear, leading to the production of atherosclerosis-associated endothelial inflammatory signaling molecules and activation of the NF-κB signaling pathway [91]. Recent studies have demonstrated the distinction between these two biological processes [32]. Turbulence-generated blood flow shear activates Piezo1, which promotes Ca2+ release. It binds to the Gq/G11-coupled P2Y2 receptor and activates the focal adhesion kinase (FAK) and NF-κB signaling pathways in the presence of PI-3 kinase (PI3K), thereby promoting the development of atherosclerosis. Additionally, integrin activation triggers phosphodiesterase 4D (PDE4D), which exerts an inhibitory effect on cAMP, leading to a reduction in cAMP-dependent kinase activation by eNOS and inhibition of vasodilation [92].

p38MAPK signaling pathway

Fibroblast-secreted IL-6 promotes cardiac hypertrophy and plays a crucial role in damaged cardiac tissues. The p38MAPK signaling pathway is activated in the pathological heart and is involved in cardiac signaling [93]. Activation of Piezo1 in cardiac fibroblasts, through pharmacological agonists or stretch stimulation, promotes an increase in Ca2+ influx. This leads to downstream activation of p38MAPK, which results in increased expression and secretion of IL-6 [31]. The cascade of Piezo1 and p38MAPK pathways provides new ideas for elucidating the interaction between signaling molecules involved in cardiac fibroblast differentiation and cardiac remodeling.

Piezo1 and integrins

The interaction of Piezo1 and integrins play an important role in the regulation of cardiovascular function: On the one hand, Piezo1 activation regulates integrin expression, and turbulence-generated blood flow shear activates Piezo1 to upregulate integrin α5 expression, with atherogenic phenotypes; On the other hand, integrins modulate the response to mechanical force stimulation of Piezo1, and different shear force stimulus intensities activate signaling pathways with different Piezo1/integrin interactions. High shear stress stimulates Piezo1 to regulate the interaction of fibronectin with integrin α5β1, and Piezo1 promotes increased Ca2+ influx, activation of calpain causes protein tyrosine phosphatase 1B (PTP1B) to bind to the integrin α5 subunit after dephosphorylating annexin A2 (ANXA2) at Y24, thereby activating integrin α5β1; Low shear stress stimulates the involvement of Piezo1 in regulating the interaction between collagen type IV and integrin αvβ3 through PI3K [94]. The process of cardiac fibrosis is associated with activation and phenotypic transformation of cardiac fibroblasts, and the conversion of cardiac fibroblasts into myofibroblasts has a pro-fibrotic effect. In cardiac fibroblasts, Piezo1 and integrins are involved in regulating the phenotypic transformation of cardiac fibroblasts through a mutually reinforcing positive feedback loop, which provides a new target for the treatment of myocardial fibrosis [30].

Exercise protects cardiac function through the HIPPO-YAP signaling pathway

The Hippo/YAP signaling pathway consists of three main components: upstream signaling inputs, core kinase cascades and downstream transcription factors. YAP/TAZ, as an essential component of the core kinase cascade, is important for the regulation of downstream transcription factors [95], involved in the regulation of cell proliferation and cell growth and development. Inhibition of YAP/TAZ expression reduces endothelial inflammation and delays atherogenesis and progression of atherosclerosis, which is closely related to atherogenic inflammation [95]. The regulatory effect of Piezo1 on YAP has been validated in cardiac fibroblasts [96], endothelial cells [97], cancer cells [98], osteoblasts [99], and human neural stem cells [100] in validated in a variety of tissues. In drug-induced endothelial cell inflammatory response, the expression of both Piezo1 and YAP/TAZ was found to be significantly increased. Activated Piezo1 increased YAP nuclear translocation, and inhibition of Piezo1 expression inhibited the endothelial cell inflammatory response and reduced or even eliminated YAP expression [97], suggesting that Piezo1 has the function of regulating the nuclear localization of YAP. A similar regulatory relationship between Piezo1 and YAP was shown in Liu et al. [101]. Piezo1 mediates YAP/TAZ activation and nuclear localization in cascade with the JNK signaling pathway and the MAPK classical signaling pathway to increase endothelial inflammation and contribute to the process of atherosclerosis development [102, 103]. Piezo1 is involved in the regulation of organismal valve generation and development, and plays an important role in cell differentiation during the embryonic period [104], and Piezo1 may act as a regulator of tissue mechanical properties in the zebrafish heart valve outflow tracts and flowing vascular system by regulating YAP expression and localization [105, 106]. Piezo1 regulation of YAP nuclear localization acts as a modulator of the macrophage inflammatory response [107], ultimately promoting angiogenesis and producing osteogenesis [108].

After myocardial infarction, a large number of cardiomyocytes die, and the dead cardiomyocytes have irreversible damage, which is a serious danger to cardiac function [109]. Cardiomyocyte proliferation and regeneration as potential pathways to improve cardiac function, pointing to new directions in cardiac regeneration [110]. Irisin plays an important role in improving tendinopathy by promoting the proliferation and differentiation of tendon-derived stem cells through up-regulation of YAP/TAZ expression, a process associated with ubiquitin proteasome hydrolysis [111]. Recombinant Irisin upregulates the expression of ECM proteins and angiogenic factors and promotes osteogenesis, showing its potential to improve adverse remodeling in response to mechanical stimulation [112]. Therefore, it is proposed whether Irisin can also target endogenous cardiac stem cells to induce cardiomyocyte proliferation in the heart. Although current research evidence and research techniques are insufficient to support this inference, given the important role played by YAP/TAZ in cardiac fibroblasts [96] and recent-related studies on cardiac fibroblasts reprogrammed into cardiomyocytes [113, 114], it is speculated that Irisin’s regulatory effects on YAP/TAZ and its downstream-specific transcription factors may play an important role in inducing cardiomyocyte proliferation.

Piezo1 and FNDC5/Irisin

Irisin is a skeletal muscle-derived factor and expressed in the heart, liver, and kidney. During exercise, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) induces increased expression of the membrane-bound protein precursor fibronectin type III domain-containing protein 5 (FNDC5) in skeletal muscle. FNDC5 cleaves two projects to form a new polypeptide, Irisin. In cardiac hypertrophy induced by TAC, injection of recombinant Irisin protein activated AMPK and inhibited mTOR, resulting in significant alleviation of cardiac hypertrophy and myocardial fibrosis [115]. Previous studies have shown that resistance training induces skeletal muscle Irisin secretion and activates the AMPK-PINK1/Parkin-LC3/P62 pathway, which inhibits mitochondrial oxidative stress in cardiomyocytes [116]. In oxidized low-density lipoprotein (oxLDL)-induced vascular injury, Irisin treatment inhibited endothelial cell apoptosis and improved endothelial function via the Akt/mTOR/Nrf2 signaling pathway [117]. Exercise increases the secretion of Irisin from the skeletal muscle, and then Irisin enters the target tissue through the circulation and interacts with its receptor, Integrin αV/β5, which activates signaling pathways such as AMPK, ERK1/2, MAPK, etc. and performs its biological functions [118, 119].

Activation of Piezo1 by different blood flow conditions produces different biological effects that can lead to atherosclerosis and myocardial fibrosis or atherosclerosis- and myocardial fibrosis-protective effects [120]. Our integration of Piezo1 downstream signaling pathways revealed a possible potential link between Piezo1 and FNDC5/Irisin. Integrins interact with Piezo1 as described previously. In the ECM, Irisin interacts with the integrin family and has great potential in participating in cytoskeleton regulation and cell proliferation [112, 121]. Mechanical signaling and changes in the ECM environment alter YAP/TAZ expression and nuclear translocation levels, and Piezo1 and FNDC5/Irisin may regulate the nuclear translocation of YAP/TAZ through a common molecular mechanism. In that both Piezo1 and FNDC5/Irisin regulation of organismal blood pressure is accomplished through the AKT/eNOS signaling pathway, Piezo1 mediates ATP generation to regulate AKT/eNOS to regulate blood pressure [11]; and FNDC5/Irisin activates AMPK to participate in the regulation of arterial blood pressure [122], the two may synergize to regulate blood pressure changes. Turbulence-activated Piezo1 stimulates the NF-κB signaling pathway to promote atherosclerosis development [32], whereas Irisin targets the ROS/p38MAPK signaling pathway to inhibit the activation of NF-κB and produce atherosclerosis protective effects [123]. Exercise upregulation of Irisin expression may antagonize the inflammatory response and atherogenic effects generated by aberrant activation of Piezo1 in pathological states (Fig. 4). In conclusion, the link between Piezo1 and FNDC5/Irisin is extensive, and there may be a regulatory relationship between the two, which needs more studies to further confirm.

Fig. 4
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Exercise modulates the signaling pathway mechanisms by which mechanosensitive ion channels and FNDC5/Irisin exert cardiovascular protective functions. ECM, extracellular matrix; EC, endothelial cell

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Exercise and downstream signaling pathway mechanisms of TRP channels

TRPC protein is a non-selective cation channel that can be activated by mechanical stress and phospholipase C-coupled surface receptor stimulation. Among them, TRPC3 and TRPC6 play a key role in cardiovascular remodeling. Hypoxic stimulation in mice promotes the interaction of TRPC3 and NADPH oxidase 2 (Nox2), leading to Nox2-dependent ROS production that mediates adverse cardiac remodeling. Physical exercise down-regulates the expression of TRPC3 and Nox2 in the mice heart, thereby enhancing myocardial compliance and flexibility and improving cardiac function [124]. Stretch-sensitive TRPV2 channels have a role in regulating Ca2+ concentration and cardiac function. Cardiac TRPV2 expression was increased after exercise, and TRPV2 deficiency led to decreased cardiac contractile function and a significant reduction in exercise capacity, TRPV2-KO mice were unable to complete compulsory exercise, and cardiac function was further impaired after voluntary wheel running exercise [78]. TRPV4 protein is one of the important calcium channels in vascular endothelial cells. It was found that TRPV4 mediated Irisin-induced Ca2+ influx and endothelium-dependent vasodilation, and that inhibition of TRPV4 prevented Irisin-induced increases in Ca2+ concentration and vasodilatory dysfunction [80] (Fig. 4).

Conclusions and prospects

The mechanosensitive cation channel Piezo1 plays an important role in the regulation of cardiovascular function, and as one of the mediators regulating the cardiovascular mechanical transduction process, research on Piezo1 has certain basic and clinical application value. In the normal heart, Piezo1 responds to appropriate mechanical stimulation to improve cardiac contractility and participates in the regulation of blood pressure, while Piezo1 deficiency is detrimental to vascular development and embryonic lethality; in the pathological heart, Piezo1 can improve ischemic damage to the heart and produce an atherosclerosis-protective effect. FNDC5/Irisin responds to the cardiovascular protective effects of exercise by increasing myocardial contractility and improving mitochondrial function. Piezo1 has a role in regulating the localization of the YAP nucleus, and aberrant activation of Piezo1 promotes the translocation of the YAP nucleus to generate an inflammatory response and is atherogenic. Mechanistic studies have found that regulation of YAP by Piezo1 and Irisin involves the intersection of multiple signaling pathways and a high degree of involvement of the integrin family, but direct evidence of exercise-stimulated myocardial Piezo1 regulation of YAP activity has not been clarified. In addition, exercise stimulates Irisin secretion, and in addition to targeting integrin αV/β5, whether other specific receptors are involved in exerting oxidative stress and apoptosis inhibition, autophagy modulation, and YAP function is not known. These are also hot issues for future research. This paper reviews the relationship between exercise, mechanosensitive ion channels, FNDC5/Irisin, YAP and cardiac protection from a new perspective, and proposes that exercise improves cardiovascular function by stimulating the mechanosensitive channels and that Irisin may play a role in this process, providing theoretical basis for cardiovascular disease prevention and cardiac rehabilitation of clinical patients.